PATHOPHYSIOLOGY OF KIDNEY.KIDNEY INSUFFICIENCY

1. PATHOPHYSIOLOGY OF KIDNEY.KIDNEY INSUFFICIENCY Prof. Yu.I. Bondarenko

3. Kidneyis major organ that regulates maintenance of outcell liquid amount and persistance of constancy inner environmental in an organism • The kidneys provide such main homeostatic parameters: • isovolemia– blood volume constancy • isotonia– osmotic pressure constancy • isoionia– ionic structure constancy • isohydria – concentration hydrogen ions constancy

4. Function of kidney includes three processes: • Plasma filtration in glomerulus • Selective canalicules reabsorbtion • Hydrogen ions, ammonium and other substances secretion Structural and functional unit of a kidney, that provides these functions is nephrone

5. NEPHRON

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12. Filtration disorder • Glomerules filtration processis pushingof water and saltes through molecularsieve under action of arterial pressure in the capillaries • It is passive process dependingon hydrostatic pressure • Filtration pressure displace liquid fromcapillaryblood into canaliculus lumen and does not requireenergy • Filtrational pressure, which predetermines glomerules filtrate derivation, is equal15-25 mm Hg • Filtrational pressure in Bowman’s capsulaof healthy person is formated 120 ml of filtrate per 1 minutes, that is 180 l per one day • The glomerules filtation can bedecreased or increased

13. Reasons of filtration decrease: • 1.Hydrostatic pressuredecrease inglomerules capillaries: in general decreasing of arterial pressuredecrease (heart insufficiency, shock, collapse, hypovolemia),narrowing glomerules afferent arterioles(arterial hypertension, pain): aorta and kidneys arteries organic defeats (aorta coarctation, stenosic aorta atherosclerosis due to hypertonic illness), kidneys arteries thrombosis or embolism • 2.Plasma oncotic pressureincrease – protein blood substitutes transfusion in large volumes • 3.Intrakidney pressureincrease – canalicules block by cylinders or urinary tract by stones • 4.Glomerulus filterdisorder – quantity functioning glomerulus decrease, glomerulus membranethickening, an pores amount and diameterdecrease, basal membrane glycoproteid components autoallergic damage.

14. Consequences of filtration disorder • The most characteristic manifestations of filtration disorder are: • azotemia (accumulation in blood of nitrogen metabolic and blood residual nitrogen increase) • renal azotemic acidosis owing to delay in an organism phosphates, sulfates and organic acids • Increase of filtration resulting blood pressure increase excessive consumption water, decomplication edema or oncotic plasma pressure decrease (hepatitis, cirrhosis) • Glomerulus filter permeabilityincreasedmanifestations: • proteinuria–evacuation with urine of plasmatic proteins over physiological norm (30-80 mg/day) and appearance in urine protein fractions with molecular weight more than 70 kD • hematuria– issue erythrocytes into canalicules lumen and their appearance in urine.

15. Consequence of increased permeability of renal filter HEMATURIA – presence oferythrocytеsin urine (innormerythrocytesdontpassthroughglomerularfilter and absent in urine !!!) Hematuria renal(in glomerulonephritis)extrarenal(innephrolithiasis, traumaof kidney) Erythrocytеs that passed through basal membrane of glomerulusis changed,deformed as their “shadow”. It evidence of glomerular origin.

16. Reabsorption disorder • The daily ultrafiltrate amount, which gets into canalicules makes equal 99 % of this volume is exposed to a converse absorption mainly in proximal canalicules • Reabsorption of proteins, glucose, aminoacids, electrolytes, bicarbonates, phosphates and wateralmost completelyare accomplished • Thereabsorbtion selectivity provides kidneys epithelium ability to reabsorp one substance and simultaneously prevents the other. This function is executed by specific molecules – which are the carriers • The dependence of reabsorbtion processes on moleculesmembrane – carriers means the limited canaliculus epithelium ability to transport reabsorbed substance • If the concentration of substance in glomerulus filtrat exceeds possibilities transport system, then given substancethreshold exceeding

20. Disorder of the canalicules function Disorder of the canalicules functionis called as tubular insufficiency • Itmay be hereditary or acquired Disorder of sodium and water reabsorbtion • The increase of reabsorption is observed in fallowing case: hyperaldosteronism, oliguri stage of acute kidney insufficiency, reabsorption decrease – hypoaldosteronism, diabetes insipidus • Sodium and water reabsorption is decreased as a result of canalicules epithelium metabolism inhibition by some poisons, including medicines, in particular, mercury diuretics. Reabsorbtion is limited because of glomerulus filtrate osmotic active substances (glucose, urin), increase owing to that so-called osmotic diuresis arises (example, diabetes mellitus) • The heavy disorders of sodium and water resorbtion arise in case dystrophic and inflammatory canaliculus epithelim changes, so canalicules lose the ability to liquid concentration and cultivation. Loss of concentration ability is called hypostenuria, relative density aqual in state changes within the limit of 1,006-1,012 (norma – 1,002-1,035). If density urine is kept at 1,010level and is not changed with influence water load, it is calledisostenuria (monotone diuresis)

21. Disorder of protein reabsorption The disorder of proteins reabsorption displays withtubular proteinuria • Poisoning cadmium • Hypoxia • Burns • Septicemia • Tubularinsufficiency is characterized by the increasing of contents in urine of albumins and other proteins with weight up to 40 kD (selective proteinuria). • Dystrophic defeats canaliculuslead toappearence proteins with molecular weight more than 40 kD (unselective proteinuria) in urine

22. The glucose reabsorbtion disorders Dayly norm of glucose loss with urine- up to 1g There are renal and extrarenal glucosuria. Renal glucosuria arises as a result : • Hereditary anomalia membrane carriers deficiency enzymes hexokinase and glucose-6-phosphatase, which provide glucose canalicules reabsorption. • Equired decrease of these enzymes activity in case of chronic poisonings with lead, mercury, uranium compounds. • Experimentally it is possible to resynthesis by means of floridsine,which oppresses phosphorilation in canalicules cells. • Extrarenal glucosuria stipulated hyperglycemia which exceeds renal threshold (9.0 – 10 mmol/l). More often it is observed due to diabetes mellitus.

23. The inorganic phosphate and calcium disorderreabsorbtion have the hereditary character. • Renal phosphate diabetes is manifested with phosphaturia, calciuria, rachitis, resistance to vitamin D, canalicules sensitiviby to parathormone increase (pseudohyperparathyroidism). • Hereditary osteodystrophias are characterized with hypocalciemia, hypophosphatemia, parathormone canalicules resistance because of appropriate receptors absence ( pseudohyperparathyroidism) The aminoacids reabsorbtiondisorder • Renal aminoaciduria develops due to of the normal aminoacids contents in blood and is explained by hereditary transport or membrane molecules-carriers deficiency. • Extrarenal aminoaciduria is observed in case of increase catabolism proteins (disintegration tumor, inflammation), phenylketonuria, cystinosis, hyperglycinemia

24. Combinedtubulopathy The most known example of suchdisorders is the Fankony syndrome. • In basis of this symptomocomplexlies kidneys canalicules function generalized disorder. • Itincludes glucosuria, aminoaciduria, phosphaturia, hypercalciuria, hypernatriuria, proteinuria, proximal renal canalicules acidosis with bicarbonaturia, rachitis with resistantion to vitamin D. Disoder of secretion • The main manifestation – canaliculus acidosis due toinhibition ammonium- and acidogenesisand secretion H+-ions. • Hyperuricemia, which develops owing tourinary acid secretiondisorder and lead to gout (renal form). • Kidney functional disorders can be completed with their insufficiency.

25. Acute renal insufficiency • It is a clinical syndrome (ARI), which is characterized by significant and acute decrease of glomerular filtration rate (GFR) • NormalGFR significance – 100-140 ml/mines • Acute renal insufficiency develops, when GFR is reduced to1-10 ml/mines • Osmotic active substances in amount which is derivated easily excrete in volume water of1,5-2 l (daily diuresis) for one day with the normal diet and normal metabolism out of organism • The minimum quantity of liquid, from which they can still be excreted makes 500 ml • Acute renalinsufficiencyis characterized by such disorder renalfunctionswhendiuresisis reduced to 500 ml.This state is called asoliguria • If daily urine does not exceed 100 ml,takes place anuria

26. Acute renal isufficiency • Reasonsof the acute renal insufficiency are divided into three groups –prerenal, renal and postrenal Prerenal factors include: circulatting liquid decrease (traumatic shock, blood loss, burns, vomiting, diarrhea), dilatation of vessels and vessels capacity increase (sepsis, anaphylaxia), heart insufficiency (myocardium infarction)

27. Reasons of ARI Renal factors include: • ischemia of kidneys, action nephrotoxines (antibiotics, heavy metals, organic solvents, X-ray contrast substances), intravessels erythrocyteshemolysis, glomerulonephritis, states assosiated to pregnancy (septic abortion, eclampsia in pregnant, bleeding)

28. Reasons of ARI Postrenal factors include: • Ureters obstruction (canaliculus, bloodclots, tumor) and urinal channel obstruction (prostat hypertrophy, carcinoma). • Postrenal reasons of diuresisdecreaseare reduced ofurine outflow due to obstructionof any level of urinary way.

29. Clinical phases of ARI. • Initial phase– is a period, which courses from lesion of kidneys untill oliguria development. It takes several hours (ischemia) up to about one week (after action nephrotoxine) • Oliguric phase is characterized by acute decrease of GFR. It course last several days up to several weeks (two weeks in average ). The patients perish just in this phase • Diuretic phase is characterized by gradual increase of urine volume.Phase of recovery – period, during which renal function completely are restored, though easy or moderateGFR decreasecan be saved in some patients • Acute renal insufficiency is accompanied by highdeath, data ischemic and traumaticform about50-70 %other form – about 10-35 %

30. Chronical renal insufficiency (CRI) Symptoms chronical renal insufficiency develops in case GFR 25 % over norm • The main reasons: • primary glomerulus diseases (chronic glomerulonephritis) • the primary canaliculus diseases (chronic pielonephritis, tuberculosis) • vascular diseases (hypertonic illness, thrombosis, embolism) • diffuse connective tissue diseases (sclerodermia, nodular periarteriitis) • illness of metabolism (gout, diabetes mellitus), • obstructive nephropathy(urolithiasis, hydronephrosis), hereditary anomalies ( kidneys polycystic)

31. Pathogenesis of chronical renal failure Renal functions decrease arisedue to decrease of acting nephrons amount • The signsinitial chronical renal insufficincy ariseowing to decrease of acting nephrons mass to 50-30 % • The expressed clinicsignsarise due to decrease of acting nephrons to30-10 % • Further decrease of actingnephronsweight (is lower than 10 %) results in terminal kidneys insufficiency stage – uremia

32. Complications of renal failure • Anemia– is the most characterizedsign of chronical renal insufficiency. • Decrease of erythropoietin formation. • Increase of erythrocytes hemolys. • Uremia oppress bone marrow ability to erythropoietin reaction. • Alimentary channelbleeding. • Continuous loss blood result in deficiency iron which promotesanemia development. • Thrombocylopathy. Chronical renal insufficiency in the patients have a qualitative changes of thrombocytes.It appears asbleeding duration increase.

33. Complications of renal failure • Heartis damaged owing to hypertension. The combination of hypertension, anemia,liquid overloading and acidosis promotes heart insufficiency development. In half of patients chronical renal terminal insufficiencystage pericarditis develops • Thelung damage is performed with so-called uremic pneumonitis, which is the stagnant phenomen in vessels of peritracheal • Arterial hypertension is observed in 50 % ofterminalchronical renal insufficiency stage. It arises is connected with hyperproduction renine,and synthesis decrease of vasodilatative prostaglandins, oppression limitation sodium excretion of extracellularliquidvolume increase • Gastrointestinal disorder– anorexia, nausea, vomiting. Thebleeding from alimentary channel is often phenomenon.Their sourceare the smallsurfaceulcers, which bleeding slowly

34. Uremic encephalopathy • Sleepiness • Inability to concentration • Absent-mindness • Amnesia • Hallutinations • Delirium • Cramps

35. Osteoporosis • Decrease of phosphatesexcretion lead to increase their level in blood. • Result hydrooxiapatite is derivationand ionized calciumlevel is decreased, thus it stimulates parathyroid glands. If GFRdecrease below 25 % of norm, secondary hyperparathyreosis become obvious. • Resorbtion of bones is increasedand their density is decreased. When weight nephrones is less than 25 %, the 25-ОН-vitamin Dtransformation to the active form – 1,25 (OH)2-vitamin Dtransformation is decelerated. It is the reason of calciumdelay absorbtion in alimentary channel

36. Osteodistrophy It is includessuchdisorders: • а) fibrosis-cystoses osteitis as result of secondary hyperparathyreosis; it appears subperiosteol boneresorbtion; • b) osteomalation– bonesdefeat whichorganicmatrixmineralisation process mineralisation infringed; • c) osteosclerosis–bonedensity increase; d) osteoporosis– boneweightdecrease and microstructural, which increase bonefragility.

37. Bones change are capable to causedestructive action on organism: • Delay growthin children • Painful fractures bonesin adult • Compressednecrosis of head femoris • Skeleton deformation • Calcification of arterial medial layer • Skin calcification with intolerable itch • Periarteriitis owing tocalciumoxyapatitis precipitation, calcification

38. Uremia • Uremiais a term, which is used for chronical renal insufficiency in terminal phase. The majority of symptoms become well expressed in GFR ratio below than 10 ml/min. • Uremic syndrome pathogenesis has become subject of intensive learning for a long time. The numerous attempts were made to identify substances, which are accumulated inrenal insufficiency terminal stage and reach dangerous to the vital function.

39. Uremic toxins is nitrogen metabolismproducts. • 1. Urea; • 2. Guanidine derivates (methylguanidine, guanidinsuccinic and guanidinacetative acids, kreatine and kreatinin); • 3. Aromatic compounds (phenole, indole, aromatic amines); 4. Conjugated aminoacids, lowmolecular peptides. • In uremiadevelopment significance ispeptides hormones accumulation– parathhormone, insuline, glucagone, gastrine, vasopressine, adrenocorticotropic and somatotropic hormones. • In the kidneys is catabolysed 25 % of peptide hormones. Some effectsis stipulated compounds deficiency, which are not synthesized in uremia. Examples – erythropoietine and 1,25-dihydroxycholecalciferoldeficiency.

40. TO YOU !!! THANKS A LOT !!!